5-36876823-TC-T

Position:

• chr5-36876823-TC-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_133433.4(NIPBL):​c.-429del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 353,100 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (2 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51

Genes affected

NIPBL (HGNC:28862): (NIPBL cohesin loading factor) This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. The Drosophila protein facilitates enhancer-promoter communication of remote enhancers and plays a role in developmental regulation. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Condensins, cohesins and other complexes with chromosome-related functions also contain HEAT repeats. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and cognitive disability. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 5-36876823-TC-T is Benign according to our data. Variant chr5-36876823-TC-T is described in ClinVar as [Likely_benign]. Clinvar id is 353359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00201 (248/123444) while in subpopulation EAS AF= 0.017 (69/4058). AF 95% confidence interval is 0.0138. There are 0 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.-429del		5_prime_UTR_variant	1/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.-429del		5_prime_UTR_variant	1/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.-429del		5_prime_UTR_variant	1/46	1
NIPBL	ENST00000652901.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 247 AN: 123378 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.000269

Gnomad FIN AF: 0.000122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000612

GnomAD4 exome AF: 0.00314 AC: 721 AN: 229656 Hom.: 2 Cov.: 0 AF XY: 0.00335 AC XY: 392 AN XY: 117040

Gnomad4 AFR exome AF: 0.000774

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.000693

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.000862

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00201 AC: 248 AN: 123444 Hom.: 0 Cov.: 31 AF XY: 0.00193 AC XY: 115 AN XY: 59732

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00616

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.000270

Gnomad4 FIN AF: 0.000122

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000605

Alfa AF: 0.000184 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

De Lange syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376839773; hg19: chr5-36876925;